Processes and intermediates for quinine, quinidine and analogs thereof

ABSTRACT

Quinine, quinidine and analogs thereof, are prepared by reacting a 4-quinolyllithium compound with a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2 xi -carboxaldehyde or the corresponding quinuclidine-2-carboxylic acid alkyl ester. Also described, inter alia, is the preparation of a 4,5-erythro-5-ethyl(or vinyl)quinuclidine-2 xi -carboxaldehyde, and a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2 xi -carboxylic acid and esters thereof. The end products are useful as antimalarial and antiarrhythmic agents.

United States Patent [191 'Grethe et al.

[ Sept. '23, 1975 PROCESSES AND INTERMEDIATES FOR QUININE, QUINIDINE ANDANALOGS THEREOF v I Inventors: Guenter Grethe, North Caldwell;

Milan Radoje Uskokovic, Upper Montclair, both of NJ.

Hoffmann-La Roche Inc., Nutley, NJ.

Filed: May 2, 1974 Appl. No.: 466,422

Related US. Application Data Division of Ser. No. 166,583, July 27,1971, Pat. No. 3,823,146, which is a continuation-in-part of Ser. No.117,131, Feb. 19, 1971, abandoned, which is a continuation-in-part ofSer. No. 20,034, March 16, 1970, abandoned.

Assignee:

US. Cl. 260/284; 260/288 CE; 424/259 Int. Cl. C07D 453/00 Field ofSearch 260/288 CE, 284

References Cited FOREIGN PATENTS OR APPLICATIONS 8/1952 United Kingdom260/289 OTHER PUBLICATIONS Russian Chem.- Rev., Vol. 29, p. 49, 51,(1960).

Fieser et al., Advanced Organic Chemistry, p. 781, (1961).

Primary Examiner--Raym0nd V. Rush Assistant ExaminerMary C. VaughnAttorney, Agent, or FirmSamuel L. Welt; Bernard S. Leon; William G.Isgro [5 7] ABSTRACT 6 Claims, No Drawings PROCESSES AND INTERMEDIATES.FOR QUININE, QUINIDINEAND ANALOGS THEREOF CROSS-REFERENCE TO RELATEDAPPLICATIONS This application is a division of U.S. Pat. ApplicationSer. No. 166,583, filed July 27,1911, now Pat, No. 3,823,146, which inturn is a continuation-in-part of U.S. Pat, Application Ser. No.117,131, filed Feb. 19, 1971, now abandoned, which in turn isacontinuationin-part of U.S. Pat. Application Ser. No. 20,034,

filed Mar. 16, 1970, now abandoned.

BRIEF SUMMARY OF THE iNvENTio The invention relates to the preparationof compounds of the formulas I and II and enantiomers and racematesthereof;

wherein m is l or 2; R, is hydrogen, hydroxy, halogen, trifluoromethyl,lower alkyl, lower alkoxy, or when m is 2, with an adjacent R is alsomethylenedicity; and R is ethyl or vinyl.

In one aspect, the invention relates to the preparation of compoundsofformulas I and II, wherein R is ethyl or vinyl, by a process whichcomprises reacting the mixture of epimeric 5(R)-ethyl(or vinyl 4(S)-quinuclidine-Z-carboxaldehydes, enantiomers or race- 5 mates, with a4-quinolyllithium compound.

In another aspect, the invention relates to the preparation of compoundsof formulas .l and II, wherein R is ethyl or vinyl, by a process whichcomprises reacting the. mixture of epimeric: 5(R)-ethyl(or vinyl)-4(S)-1O quinuclidine-ZE-carboxylic acid alkyl esters, enantiomers; orracemates thereof, with a 4-quin0lyllithiurn compound and thereafterreducing-the .resulting 4- [5(R)-ethyl(or vinyl)-4(S) quinuclidin 2(R orS )ylcarbonyl]quinoline, its enantiomer or its racemate, tothe 15corresponding end product of formulas I and II.

In still another aspect, the invention relates ,to intermediates of theformulas:

CllClz and their racemates and enantiomers,

wherein R is as previously described, R is lower al- 5 kyl, aryl oraryl-lower alkyl; m is l or 2, and R, is hydroxy, halogen,trifluoromethyl, lower alkyl or lower alkoxy, or when m is 2, with anadjacent R is also methylenedioxy.

DETAILED DESCRIPTION OF THE INVENTION- The term lower alkyl as usedherein denotes a hydrocarbon group containing l7 carbon atoms, such asmethyl, ethyl, propyl, butyl and the like; methyl and ethyl arepreferred. The term lower alkoxy denotes a lower alkyl ether group inwhich the lower alkyl moiety is as described above. The term halogen"denotes all the halogens, i.e., bromine, chlorine, fluorine and iodine;chlorine is preferred. The term aryl denotes phenyl or phenyl bearingone or more substituents selected from'the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkylamino. Exemplary of aryl-lower alkyl arebenzyl, phenethyl and the like.

A process aspect of the invention is exemplified by Reaction Scheme Ia."

Scheme Ia.

CCl

wherein R is lower alkyl, aryl or aryl-lower alkyl.

v In Reaction Scheme 1a; the racemic l,l,l-trichloro-3-(3-ethyl-4-pyridinyl)propan-Z-ol of formula III [also known as3-ethyl-4 2-hydroxy-3,3,3-trichloropropyl)- pyridines] or either of itsenantiomers is converted to the mixture of racemic, epimeric cis1,1-dichloro-3-(3- 'ethyl-4-piperidinyl)propan-ZE-QIS of formulas IVaand ,VIa

VIIIa i an alkanol, such as ethanol, methanol and the like, and in thepresence of a mineral acid, such as hydrochloric, hydrobromie, sulfuricacid and the like, or an organic acid, such as acetic acid, tartaricacid and the like.

The enantiomers or racemates of epimeric cisl,ldichloro-3-(3-ethyl-4-piperidinyl)propan-25-ols of formulas lVa andVa are converted to the mixture of epia inert organic solvent, forexample, an alkanol, such as 20 methanol, ethanol and the like; ahydrocarbon, such as benzene, toluene, hexane, petroleum ether and thelike; or an ether, such as tetrahydrofuran, diethylether, dioxanc anddiglyme; or a mixture of water and an immiscible inert organic solvent,such as benzene, dichloromcthane or the like.

The mixture of epimeric 5(R)-ethyl-4(S)-quinuclicline-2g-carboxaldehydes of formula Vla, enantiomers orracemates, is converted to the mixture of epimeric5(R)-ethyl-4(S)-quinuclidine-2-carboxylic acids of formula VIla,enantiomers or racemates, utilizing an oxidizing agent. As the oxidizingagent, there can be utilized silver oxide, chromic acid, potassiumpermanganate, and the like. The oxidation is conveniently carried out atroom temperature or below, and if desired, in the presence of a solventsuch as an alkanol or water The mixture of epimeric 5(R)-ethyl-4(S)-quinuclidine-2f-carboxylic acids of formula Vlla, enantiomers orraeemates, is converted to the mixture of epimeric5(R)-ethyl-4(S)-quinuclidine-2-carboxy]ic acid alkyl esters of formulaVllla, enantiomers or race mates, utilizing an esterifying agent. As theesterifying agent, there can be utilized alkanols such as ethanol,methanol, and the like, in the presence of an acid such as hydrogenchloride, sulfuric acid and the like. The esterification is convenientlycarried out at a temperature in the range of between about roomtemperature and the boiling temperature of the reaction mixture.

Still another process of the invention is exemplified by Reaction Schemelb:

Scheme. Ib

CHO

N A 0 c n CliClz CHClz a 1, R2 a H N v one VIII VII wherein R and are aspreviously described.

In Reaction Scheme lb the N-ben zoyl-3(R)-ethyl( orvinyl)-4(S)-piperidineacetaldehyde of formula IX, its enantiomer or.racemate, is converted to the corre' sponding mixture of epimericl,1-dichIoro-3-[3( R)- ethyl(or vinyl)-4(S)-piperidinyl]propan-2-ols offormulas IV and V, enantiomers or racemates, utilizing a Grignardreagent, such as dichloromethyllithium. The

reaction is conveniently carried out at room temperature and below roomtemperature, preferably between about 0 and about -7,0C. Moreover, thereaction can be suitably carried out in the presence of an inert organicsolvent, for example, an ether, such as tetrahydrofuran, diethylether,dioxane and diglyme; or a hydrocarbon such as benzene, toluene, hexane,petroleum ether andthe like.

The mixture of epimeric l,l-dichloro-3-[3(R)- ethyl(orvinyl)-4(S)piperidinyl]propan-2E-ols of formulas IV and V, enantiomersor racemates, are converted to the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2- carboxaldehydes of formula VI, enantiomersor racemates, by the procedure previously described for the compounds offormulas lVa and Va.

The mixture of epimeric 5(R)-ethyl(or vinyl)-4(S)-quinuclidine-2tf-carboxaldehydes of formula VI, enantiomers orracemates, is converted to the imixture of epimeric 5(R)-ethyl( orvinyl)-4(S)-quinuclidine-2 carboxylicacids of formula VII, enantiomersorrace mates, the procedure previously described for the compoundofforrnula Vl a. u p Y quinuclidineQg-carboxylic acids of formula VII,enantiomers or racemates thereof, is converted to the' mix- I viriyI)'-4( S)-" ture of" epimeric 5(R)ethyl( oij quinuclidine-2fi-carboxylicacid' alky'l estersof formula VIII, enantiomers or racemates thereof,by'the proc' dure previously described for the cor'hpo u ndof VIIa.

A further process aspect of the-invention is exemplified by ReactionScheme lIzi :1 t.

SchemeIIQ enantiomers and racemates thereof,

wherein R R and m are as previously described.

In Reaction Scheme 11, the mixture of epimeric 5(R)- ethyl(orvinyl)-4(S)-quinuclidine-Z-carboxaldehydes of formula VI, enantiomers orracemates thereof, is reacted with -a 4-quinolyllithium compound offormula X to yield the corresponding a(S)-[5(R)-ethyl(or vinyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula I, enantiorneror racemate thereof, and a(R)- vinyl)-4(S)-quinuc1idin-2(S)-y1]-4-quinolinemethanol of formula II, enantiomcr or racemate thereof. The4-quinolyllithium compound of for-' mula X is reacted in equimolar orgreater than equimolar proportions with the compound of formula VI.Preferably, tow molar proportions of the quinolyllithium compound areutilized. The reaction is conveniently carried out at room temperatureor below room temperature, preferably at a temperature in the range ofbetween about 0 and about 70, in the presence of an inert organicsolvent, for example, an ether, such as diethylether, tetrahydrofuran,dioxane and diglyme; or a hydrocarbon, such as benzene, toluene and thelike. The reaction is conveniently carried out in the presence ofcomplexing agents such asv 1,4- diazabicyclo[2.2.2] octane ortetramethylethylenediamine.

Representative of the compounds of formula X are the following:

4-quinolyllithium; 6-methoxy-4-quinolyllithium;6-methyl-4-quinolyllithium; 7-methoxy-4-quinolyllithium;6,7-dimethoxy-4-quinolyllithium; 6,7-methylenedioxy-4-quin0lyllithium;6,8-dimethoxy-4-quinolyllithium; 6-chloro-4-quinolyllithium;7-trifluoromethyl-4-quinolyllithium; 7-chloro-4-quinolyllithium;6,8-dichloro-4-quinolyllithium; and the like. Since the foregoing4-quinolyllithium compounds are highly labile, it is preferred toprepare them in situ, by reacting the corresponding 4-bromoquinolinewith, for example, n-butyllithium in the presence of a solvent, forexample, a hydrocarbon, such as benzene, toluene, hexane, petroleumether; or an ether, such as dioxane, ether, diglyme, tetrahydrofuran andthe like. Exemplary of the 4-bromoquinoline compounds are: 4-bromoquinoline;

4-bromo-6-methoxyquinoline; 4-bromo-6-methylquinoline;4-bromo-7-methoxyquinoline; 4-bromo-6,7-dimethoxyquinoline;4-bromo-6,7-methylenedioxyquinoline; 4-bromo-6,8-dimethoxyquinoline;4-bromo-6-chloroquinoline; 4-bromo-7-chloroquinoline;4-bromo-6,8-dichloroquinoline; 4-bromo-7-trifluoromethylquinoline; andthe like. The 4-halo-quinolines can be prepared by known procedures fromthe corresponding 4-hydroxyquinolines, exemplary of which are:

4-hydroxyquinoline; 4-hydroxy--methoxyquinoline;4-hydroxy-6-methylquinoline; 4-hydroxy-7-methoxyquinoline;4-hydroxy-6,7-dimethoxyquinoline; 4-hydroxy-6,7-methylenedioxyquinoline;4-hydroxy-7trifluoromethylquinoline; 4-hydroxy-6,8-dimethoxyquinoline;4-hydroxy-6-chloroquinoline; 4-hydroxy-7 hloroquinoline;4-hydroxy-6,8-dichloroquinoline; and the like. Yet another aspect of theinvention is exemplified by Reaction Scheme Ill.

Scheme III VIII wherein R R R and m are as previously described.

In Reaction Scheme III, the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2g-carboxylic acid alkyl. esters of formulaVIII, enantiomers or racemates, is reacted with a 4-quinolyllithiumcompound of formula X to yield the corresponding mixture of epimeric4-[5(R)-ethyl(or vinyl)-4(S)-quinuclidin-2- ylcarbonyl]quinolines offormula XI, enantiomcrs or racemates thereof. The 4-quinolyllithiumcompound of formula X is reacted in equimolar or greater than equimolarproportions with the compound of formula VIII. Preferably, two molarproportions of the quinolyllithium compound are utilized. The reactionis conveniently effected at room temperature or below room temperature,preferably in the range of about between 0 and about 70C. Suitably, aninert solvent, for example, an ether, such as diethyl ether,tetrahydrofuran,'

dioxane and diglyme, or a hydrocarbon such as benhydride, such asdiisobutylaluminum hydride or the like. The reduction is suitablycarried out at room temperature; however, temperatures above or belowroom temperature may be employed. It is preferred to employ atemperature between and 50C. The reduction can be conveniently conductedin the presence of an inert organic solvent, for example, a hydrocarbonsuch as benzene or toluene, or an ether such as diethylether,tetrahydrofuran or the like.

The conversion of the compounds of formula XI, enantiomers or racematesthereof, to those of formulas I and II, enantiomers or racematesthereof, respectively,

when R is ethyl, can also be effected utilizing a hydrogenation catalystsuch as nickel, palladium, ruthenium, copper or barium chromite in thepresence of a solvent, for example, an aqueous or non-aqueous alkanolsuch as methanol or ethanol, or an ether such as dioxane. When R isethyl or vinyl, the conversion can be effected utilizing a hydrogenationagent such as aluminum in ethanol, sodium isopropoxide in toluene,sodium or potassium borohydride in methanol, ethanol, isopropanol ortetrahydrofuran, lithium aluminum hydride, aluminum hydride,chloroaluminum hydride, dichloroaluminum hydride, bromoaluminum hydride,dibromoaluminum hydride, lithium tri-tert.- butoxyaluminum hydride inether, tetrahydrofuran, dioxane or the like.

The compounds of formulas I and II and their pharmaceutically acceptableacid addition salts possess antimalarial and antiarrhythmic propertiesand are therefore useful as antimalarial and antiarrhythmic agents.Their pharmacologically useful antiarrhythmic activity is demonstratedin warm-blooded animals utilizing standard procedures, for example, thetest compound is administered to prepared mongrel dogs. The chest cavityof the experimental animal previously anesthetized using a combinationof sodium barbitol, 300 mg/kg. and pentobarbitol, 15 mg/kg, i.v., isopened up through the third right interspace under artificialrespiration and the pericardium is cut and sutured to the wall of thethorax so as to maintain the heart in a pericardial cradle throughoutthe course of the test procedure. Arterial pressure is monitored byinserting a polyethylene cannula into the aorta via the left carotidartery and is measured with an appropriate Statham pressure transducer.During the course of the experiment, electrical activity of the heart isviewed both on an oscilloscope and recorded on a Sanborn polyviso usingstandard EGG lead II. The heart is also observed visually. Theantiarrhythmic assay of the test drug is undertaken using a modificationof the method of Scherf and Chick, Circulation, 3 764-769 (I951). Adripping of 1 percent solution of acetylcholine is applied to the sinusnode and the atrium is irritated by pinching with a pair of forceps.This procedure produces a continuous atrial arrhythmia which mostlyconsists of atrial fibrillation.

Since hypokalemia produces a susceptibility to atrial fibrillation(Leveque, Arch. Int. Pharmacodyn, 149, 297- 307, 1964), 2 units/kg. ofinsulin is administered 30 minutes before the start of the acetyleholinedrip. Once atrial fibrillation is established, there is a tenminutewaiting period before the test drug is administered. The test drugs areadministered intravenously at the rate of l mg/kg/minute until normalsinus rhythm appears or until 30 mg/kg. of drug is administered.

The pharmacologically useful antimalarial activity of the aforementionedcompounds is demonstrated in warm-blooded animals using standardprocedures, for example, the test substance is administered to albinomice in variable amounts. Albino mice are inoculated with about 10million red cells infected with P. Berghei. Treatment is started on thefirst day after inoculation, and the drug is administered per os during4 consecutive days. On the seventh day of infection, smears are made,stained with giemsa and microscopically examined for P. Berghei.

When racemic 7-methoxy-dihydrocinchonidine dihydrochloride and racemic7'-methoxydihydrocinchonine dihydrochloride are utilized as the testsubstance at dosages in the range of mg/kg. to about 250 mg/kg., themicroscopical examination of the blood smears is free of P. Berghei(negative).

The compounds of formulas I and II, which include quinine and quinidineand their dihydroanalogs, have effects quantitatively similar, forexample, to those of quinine and quinidine of known therapeutic uses andproperties. Thus, the compounds prepared by the process of the inventiondemonstrate a pattern of activity associated with antimalarials andantiarrhythmics of known efficacy and safety.

The compounds of formulas I and II form pharmaceutically acceptable acidaddition salts and such salts are also within the scope of thisinvention. Thus, the aforementioned compounds form pharmaceuticallyacceptable addition salts with, for example, both pharmaceuticallyacceptable organic and inorganic acids, such as acetic acid, succinicacid, formic acid, methanesulfonic acid, p-toluene-sulfonic acid,hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and thelike.

The products of the process of the invention can be incorporated intostandard pharmaceutical dosage forms, for example, they are useful fororal or parenteral application with the usual pharmaceutical adjuvantmaterials, e.g., organic or inorganic inert carrier materials such aswater, gelatin, lactose, starch, magnesium stearate, talc, Vegetableoils, gums, polyalkyleneglycols, and the like. The pharmaceuticalpreparations can be employed in a solid form, e.g., as tablets, troches,suppositories capsules, or in liquid form, e.g., as solutions,suspensions or emulsions. The pharmaceutical adjuvant materials caninclude preservatives, stabilizers, wetting or emulsifying agents, saltsto change the osmotic pressure or to act as buffers. They can alsocontain other therapeutically active materials.

The following examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 6,7-methylenedioxy-4-quinolinol A suspension of50 g. of 4-hydroxy-6,7- methylenedioxyquinoline-3-carboxylic acid in 500ml. of freshly distilled quinoline was heated at 200 until the evolutionof gas ceased. The reaction mixture was cooled to room temperature,diluted with an equal amount of ether and kept cool overnight. Theprecipitated brown solid (51.4 g., m.p. 254267) was collected byfiltration and dissolved in refluxing ethanol. The insoluble materialwas removed and the ethanol solution was reduced to /a of its volume.The solution was diluted with an equal amount of ether. On cooling, 31.1g. of 6,7-methylenedioxy-4-quinolinol separated, m.p. 280282.Recrystallization (2x) from hot water yielded analytically pure6,7-methylenedioxy-4- quinolinol as a pale yellow solid, m.p. 288289.

Analysis Calcd. for C H NO (189.16); C, 63.49; H, 3.73; N, 7.41; Found:C, 63.58; H, 4.04; N, 7.34.

EXAMPLE 2 Preparation of 4-bromo-6,7-methylenedioxyquinoline To a slurryof 10 g. of 6,7-methylenedioxy-4- quinolinol and 10 ml. of phosphorustribromide, preheated to 60, was added 4 ml. of phosphorus oxybrornide.The mixture was heated at 150. After 1 hour, an additional 4 ml.phosphorus oxybromide was added and heating was continued for 2 hourswith occasional stirring. The mixture was cooled to room temperature andcarefully added to 1 l. of vigorously stirred crushed ice. Theprecipitate was collected by filtration and, after washing with water,was suspended in 100 ml. of water. The suspension was rendered alkalineby the addition of solid sodium bicarbonate. The precipitate wascollected by filtration, washed with water and extracted thoroughly withchloroform. The organic extract was dried over sodium sulfate andevaporated to dryness to yield a-nearly colorless solid which onsublimation at 100-l20 and 0.35 mmHg gave 8.3 g. of 4-bromo-6,7-methylenedioxyquinoline, m.p. 147149.

Analysis Calcd. for C H BrNO (252.08); C, 47.65; H, 2.40; N, 5.56;Found: C, 47.57; H, 2.30; N, 5.42.

EXAMPLE 3 Preparation of 4-bromo-6,8-dichloroquinoline A paste preparedfrom 33 g. of 6,8-dichloro-4- quinolinol and 50 ml. of phosphorustribromide was heated to 60. After adding 20 ml. (56 g. of phosphorusoxybromide, the mixture was maintained at 150 for 3 hours withoccasional stirring. Then, the mixure was cooled and added carefully to1.5 1. of vigorously stirred crushed ice. The aqueous suspension wasrendered alkaline by the addition of 12N sodium hydroxide. Theprecipitate which formed was collected by filtration and dried in avacuum oven. Sublimation of the dried material at and 0.3 mmHg yielded35.7 g. of crystalline 4-bromo-6,8-dichloroquinoline, m.p. 163-165.Recrystallization from ether gave pure 4- bromo6,8-dichloroquinoline,m.p. 164-l 66.

Analysis Calcd. for C H BrC1 N (276.97); C, 39.03; H, 1.46; H, 5.05; Cl,25.60; Found: C, 39.03; H, 1.32; N, 5.04; Cl, 25.61.

EXAMPLE 4 Preparation of l l l-trichloro3-(3-ethyl-4-pyridinyl)propan-2(R)-ol and 1 ,1,l-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol To 106.6 g. of1,1,l-trichloro-3-(3-ethyl-4- pyridinyl)propan-2-ol dissolved in 1.2 l.of hot acetone was added a solution of 65.2 g. of d-tartaric acid in ll. of acetone. Upon cooling, crystalline material separated (66.8 g.)which after fractional crystallization from acetone, yielded pure1,1,1-trichloro-3-(3-ethyl- 4-pyridinyl)propan-2(R)-ol d-tartrate, m.p.176-177.5, [a],, 30.7 (c 0.960, ethanol).

Analysis Calcd. for C ,,1-l C1 No.C,,H O (418.67) C, 40.16; H, 4.33; N,3.35; C1, 25.40; Found: C, 39.97; H, 4.18; N, 3.23; Cl, 25.59.

The tartrate salt was dissolved in water. The solution was renderedalkaline with a saturated aqueous solution of sodium carbonate andextracted four times with dichloromethane. The combined organic extractswere dried over sodium sulfate and evaporated to dryness under reducedpressure to give 1,1,1-trichloro-3-(3- ethyl-4-pyridinyl)propan-2(R)ol,m.p. l32134, [01],, 45.1 (c 1.025, ethanol) after recrystallization fromether.

Analysis Calcd. for C H C1 NO (268.58); C, 44.72; H, 4.51; N, 5.22; Cl,39.60; Found: C, 44.99; H, 4.59; N, 4.96; Cl, 39.62.

The mother liquors obtained from the fractional crystallization werecombined and evaporated to dryness. The resulting residue was dissolvedin 4 l. of water. Insoluble material was removed by filtration, and thesolution wasrendered alkaline with 6N sodium hydroxide. The resultingsolution was extracted three times with dichloromethane. The combinedorganic extract was washed three times with water, dried over sodiumsulfate and evaporated to dryness to give 57.2 g. of a brown solid. Asolution of this material in 800 ml. of ac etone was combined with asolution of 31.8 g. of 1- tartaric acid in 700 ml. of acetone. Uponcooling, 54.9 g. of crystalline tartrate separated. Fractionalcrystallization of this material from acetone yielded pure 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol ltartrate, m.p. 177l78,[01],, 30.3 (c 1.065, ethanol).

Analysis Calcd. for C H Cl NO.C,H O l(418.67); C, 40.16; H, 4.33; N,3.35; Cl, 25.40, Found: C, 39.83; H, 4.63; N, 3.29; C1, 25.32.

Pure 1 ,1 ,1-trichloro-3-(3-ethyl-4-pyridinyl)propan- 2(S)-ol obtainedfrom l,l,1-trichloro-3-(3-ethyl-4- pyridinyl)propan-2(S)-ol l-tartrate,as described above for the preparation of the other enantiomer had amelt- 3,907,806 16 ing point of 132l34, [01],, 45.5 (c, 1,020, etha-EXAMPLE 6 nol) after recrystallization from ether.

Analysis Calcd. for C, H, Cl NO (268.58); C, 44.72; H, 4.51; N, 5.22;Cl, 39.60; Found: C, 45.05; H, 4.51; N, 5.04; Cl, 39.32. 5

Preparation of 1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]-propan-2(R)-o1 hydrochloride (A) and 1, l -dichloro-3-[ 3(R)-ethyl-4(S)-piperidinyl Jpropan- 2(R)-ol hydrochloride (B) H CH l (A) H .l-lClEXAMPLE 5 A solution of 2.7 g. of 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl) propan-2(R)-ol (C) in ml. of 5 percent aqueous hydrochloricacid was hydrogenated over 0.4 Preparation of racemic g. of platigitmoxidp at t60-90" atnd 65 atmospthlerestof l,l d-

3 3 R l 4 S d 1 pressure. 61' C00 lng 0 room empel'a ure, 6 Ca a" t gzgg 1 ori g gz gl gfi 4O lyst was removed by filtration, and the resultingfiltrate I,1 dichloro 3 l3(R) ethyl 4(s) piperidinyl]propan wasevaporated under reduced pressure. The residue 2(R) O1 hydrochloride wascrystallized from 40 ml. of ethanol to give 600 mg.

of l ,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(R)-olhydrochloride, m.p. 232- 233, [04],, a Solunon of raceimc +29.63 (01.0953, methanol) after recrystallizationtr1chloro-3-(3-ethy1-4-pyr1dmyl)propan-Z-ol m 400 ml. from ethanolAnalysis Calcdfor COHISC12NOHO of 5 percent aqueous hydrochloric acidwas added 4 g. (276 65) C 43 H 7 N 5 Found C 43 l of platinum dioxideand the mixture was hydrogenated H 7 at 60C and 67 atmospheres ofpressure After coolmg The mother liquors were concentrated andcrystallito room temperature i Catalyst was removed by a zation of theresidue from acetone gave 557 mg. of 1,1- tration, and the resultingfiltrate was evaporated 1n 5 dichlom 3 [3(R) ethyl 4(S) piperidinyl]plOpan 2(R) vacuo. The residue was crystallized from 70 ml. of aloolhydrochloride mp. 16804700, [041"25 +2529, (c Solute ethanol to give 105(38 percent) of racemlc 1.0140, methanol), after recrystallization fromace- 1,1-dichloro-3-[3(R)-ethyl4(S)-piperidinyl]propantone 2(S)-Olhydrochloride, having a melting point of Analysis Calcd. forCIOHIQCIZNOIHCI C, 200-205, after recrystallization, m.p. 205-209. 4342;H, 7 7 N 50 Found: C, 4355; H 747; N

Analysis Calcd. for C H Cl NO (276.64), C, 43.42; 5.00. I

H, 7.29; Cl, 38.55; N, 5.06; Found: C, 43.69; H, 7.25; CI, 3 835; N,5.22.

Crystallization of the mother liquors from 30 m1. of acetone gave 9.5 g.(34.5 percent) of racemic 1,1-

dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)- EXAMPLE 7 olhydrochloride, having a melting point of 123129 Preparation of after tworecrystallizations, m.p. l32-l34.1,l-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl] Analysis Calcd. for col'lgoclaNo (276.64); C, 43.42; propan-2 (S)-ol hydrochloride (D) and H,7.29; CI, 38.55; N 5.06, Found: C, 43.38; H, 7.41;l,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan- Cl, 38.37; N, 4.86.2(S)-ol hydrochloride (E) A solution of 2.7 g. of l,l,1-trichloro-3-(3-ethyl-4- pyridinyl)propan-2(S)-ol (F) in 40 ml. of 5 percent aqueoushydrochloric acid was hydrogenated over 0.4 g. of platinum oxide at 60and 65 atmospheres of pressure. After cooling to room temperature, thecatalyst was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was crystallized from ml. of ethanolto give 600 mg. of 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)- o1 hydrochloride,m.p. 227'-229. Several recrystallizations from ethanol yielded purel,l-dichloro-3- [3(R)-ethyl-4(S)-piperidinyl]-propan-2(S)-olhydrochloride, m.p. 232-233, [04],, 28.3 (0 1.0237, methanol) AnalysisCalcd. for C I-I Cl NOHCI (276.65); C, 43.42; H, 7.28; N, 5.06; Found:C, 43.58; H, 7.32; N, 5.08.

The free base obtained from 1,l-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloride on treatment withaqueous potassium carbonate and extraction with dichloromethane, wascombined with ethanolic hydrogen bromide to give 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrobromide, m.p. 223-224,[01],, 24.77 (0, 0.9486, methanol), after several recrystallizationsfrom ethanol.

Analysis Calcd. for c H cl NQHBr (321.11); C, 37.41; H, 6.28; N, 4.36;Found: C, 37.71; H, 6.44; N, 4.46.

The mother liquors obtained from the crystallization of l, l-dichloro-3-[ 3( R)-ethyl-4(S)-piperidinyllpropan-2(S)-ol hydrochloridewere combined and concentrated under reduced pressure. The residue wastriturated with acetone and the crystalline material was recrystallizedfrom acetone to give 729 mg. of 1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(S)- o1 hydrochloride.Recrystallization from acetone yielded l, 1 -dichloro-3-[3(S)-ethyl-4(R)-piperidinyl 1- propan-2(S)-ol hydrochloride, m.p.l69.5l7l.5, [M 25.l5 (0, 0.9306, methanol).

Analysis Calcd. for C H Cl NQHCl (276.65); C, 43.42; H, 7.28; N, 5.06;Found: C, 43.69; H, 7.49; N, 5.34.

EXAMPLE 8 Preparation of 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]-propan- 2(S)-olhydrochloride and 1 ,1-dichloro-3-[ 3(R)-vinyl-4(S)-piperidinyl]propan-2(R)-ol hydrochloride To a solution containing 3.07 ml. of methylenechloride in 60 ml. of anhydrous tetrahydrofuran cooled to there wasadded over a period of 1 hour 44 mmoles of n-butyllithium in 28 ml. ofhexane under an atmosphere of dry nitrogen. Stirring of the mixture atthe same temperature was continued for 20 minutes and then followed bythe dropwise addition of 5.19 g. (20 mmoles) of 2-[l-benzoyl3(R)-vinyl-4(S)- piperidinyl]acetaldehyde in 30 ml. ofanhydrous tetrahydrofuran. After 30 minutes, the reaction was quenchedby the addition of 30 ml. of water. The mixture was allowed to warm upto room temperature and was subsequently extracted three times withether. The combined ether extracts were washed with water, dried oversodium sulfate and evaporated to dryness. The residue was dissolved in80 ml. of 3N hydrochloric acid. The acidic solution was washed withether and neutralized with 3N sodium hydroxide. The solution was washedagain with ether, rendered alkaline by the addition of 3N sodiumhydroxide and extracted with ether. The ether extract was washed withwater, dried over sodium sulfate and evaporated to dryness. The residue(3.8 g. was dissolved in ethanol and treated with an excess of ethanolichydrogen chloride. The solvent was evaporated under reduced pressure andthe resulting solid residue was crystallized from ethanol to give 2.0 g.of a mixture of epimeric l,l-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2-ol hydrochlorides. Fractionalcrystallization from ethanol followed by recrystallization of thecombined fractions from ethanol gave 1, l -dichloro-3-[ 3(R)-vinyl-4(Spiperidinyl ]propan-2( S )-ol hydrochloride, m.p. 225225.5, [01],, l3.3(c 1.02, methanol).

Analysis Calcd. for c H Cl NQHCl (274.62); C, 43.74; H, 6.61; N, 5.10;Found: C, 43.71; H, 6.53; N, 4.85.

The mothor liquors were combined and evaporated to dryness.Recrystallization of the residue from acetone gave 1, l -dichloro-3-[3(R)-vinyl-4(S piperidinyl]propan-2(R)-ol hydrochloride, m.p. l65l67,[a],, 30.7 (c 1.00, methanol).

Analysis Calcd. for C H CI NOHCI (274.62); C, 43.74; H, 6.61; N, 5.10;Found: C, 44.01; H, 6.86; N, 4.78.

EXAMPLE 9 Preparation of l, 1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan2(S)-ol hydrochloride and 1, l -dichloro-3-[ 3(R)-ethyl-4(S )-piperidinyl ]propan- 2(R)-ol hydrochloride To a solutioncontaining 6.35 ml. of methylene chloride in 120 ml. of anhydroustetrahydrofuran cooled to 70 there was added over a period of 2 hours 90mmoles of n-butyllithium in 55.5 ml. of hexane under an atmosphere ofdry nitrogen. The mixture was stirred at the same temperature for 30minutes and then followed by the dropwise addition of 5.8 g. (22.4mmoles) of 2-[ l-benzoyl-3 R)-ethyl-4( S piperidinyl]acetaldehyde in 60ml. of anhydrous tetrahydrofuran. After 30 minutes, the reaction wasquenched by the addition of 30 ml. of water. The mixture was allowed towarm to room temperature and was subsequently extracted three times withether. The combined ether extracts were extracted with 300 ml. ofpercent aqueous hydrochloric acid. The acidic solution was washed twicewith each 100 ml. of ether and evaporated to complete dryness. Theresidue was dissolved in the minimal amount of hot ethanol. Uponstanding, there was obtained 1.1 g. of 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydro- M chloride, mp239240, [011 Q 28.6(c 1.005, methanol), after recrystallization fromethanol.

The mother liquors were combined and evaporated to drynessRecrystallization of the residue from acetone gavel,ldichloro-3-[3(R)-ethyl-4(S)- piperidinyl]propan-2(R)-olhydrochloride, mp l72-l73, [041 Q +25.2 (c 1.00 methanol).

EXAMPLE 10 Preparation of epimeric, racemic4,S-erythro-5ethylquinuclidine-2-carboxaldehydes a. To a solutioncontaining 2.77 g. of racemic 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)- ol HCl in 20 ml. ofmethanol was added a solution containing 1.68 g. of potassium hydroxidein 15.8 ml. of methanol. The mixture was stirred at room temperature for55 hours. The precipitate formed in the reaction was removed byfiltration, and the filtrate was evaporated to dryness. The residue wastreated with 200 ml. of ether, and the insoluble part was removed byfiltration. The filtrate was evaporated to dryness to yield an oilymixture of epimeric, racemic 4,5-erythro-5ethylquinuclidine-2-carboxaldehydes. b. The methanolic solutioncontaining crude aldehyde prepared as above from 5.45 g. of racemicl,l-dichloro-3-[3(R)- ethyl-4( S )-piperidinyl ]propan-2(S )-olhydrochloride was evaporated to dryness under reduced pressure at atemperature below 30. The residue was dissolved in 300 ml. of ether,insoluble material was removed by filtration, and evaporation of thefiltrate gave 4.12 g. of oily residue. A solution of the residue in ml.of ether was added to a solution containing 2.5 g. of sodium bisulfitein 8 ml. of water. The solvents were removed under reduced pressure, andthe residue was dissolved in 10 ml. of water. Addition of ethanolfollowed by the addition of ether precipitated 3.4 g. of solid additionproduct. This product was added to 50 ml. of saturated aqueous solutionof sodium carbonate and heated at 40. After all material had dissolved,the solution was kept at 40 for another 5 minutes. The mixture wascooled and extracted three times with ether. The combined ether extractswere dried over potassium carbonate and evaporated to dryness underreduced pressure to give 950 mg. of liquid aldehyde. Distillation in ashort path distillation apparatus at 6085 (oil bath temperatures) undera pressure of 0.4 mml-lg. gave 648 mg. of analytically pure mixture ofepimeric, racemic 4,5-erythro-5-ethylquinuclidine-2- carboxaldehydes.

Analysis Calcd. for C H NO 167.24); C, 71.81; H, 10.25; N, 8.38; Found:C, 71.91; H, 10.02; N, 8.58.

c. A solution containing 1.39 g. of racemic 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl)propan-2(R)- o1 HCl in 25 ml. ofwater was combined with ml. of benzene. The stirred mixture was cooledin an ice bath and 8.56 ml. ofa 1.75N potassium hydroxide solution wasadded slowly. Stirring at room temperature was continued underatmosphere of nitrogen for 20 hours. The aqueous layer was separated andextracted with benzene. The combined organic layer was dried over sodiumsulfate and evaporated under reduced pressure at approximately 30, Theresidue was distilled in a short path distillation apparatus at 6085(oil bath temperature) and 0.3 mmHg. to give 600 mg. (72 percent) of amixture of epimeric, racemic 4,5-erythro-5ethylquinuclidine-2-carboxaldehydes. d. To a solution of 400 mg. ofracemic, epimeric cis l, l -dichloro-3- with benzene. The benzenesolution was dried over 1 MgSO and evaporated to dryness under reducedpressure to give epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2-carboxaldehydes.

EXAMPLE 11 Preparation of epimeric 5 R )-ethyl-4( S)-quinuclidine-2-carboxaldehydes a. A solution containing 1.14 g. of1,1-dichloro-3- [3(R)-ethyl-4(S) piperidinyl]propan-2(S)-olhydrochloride in 20 ml. of water was combined with 450 ml. of benzene.The stirred mixture was cooled in an ice bath and 7.4 ml. of a 1.68Npotassium hydroxide solution was added slowly. Stirring at roomtemperature was continued under an atmosphere of nitrogen for 20 hours.The aqueous layer was separated and extracted with benzene. The combinedorganic layer was dried over sodium sulfate and evaporated under reducedpressure at 30. The residue on evaporative bulb-tobulb distillation at80 and 0.1 mmHg yielded 283 mg. of liquid epimeric5(R)-ethyl-4(S)-quinuclidine-2- carboxaldehydes, [:1 2 +102.6l (c.1.1383, methanol).

Analysis Calcd. for C H NO (167.24); C, 71,81; H, 10.25; N, 8.38; Found:C, 71.75; H, 9.97; N, 8.44.

b. Utilizing the procedure above, a mixture of 1.94 g. of 1, l-dichloro-3-[ 3 R )-ethyl-4( S )-piperidinyl 1 propan-2(S)-olhydrochloride and l,l-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)ol hydrochloride gave afterevaporative bulb-to-bulb distillation at 80 and 0.3 mmHg 538 mg. ofepimeric 5(R)-ethyl-4(S)- quinuclidine-2g-carboxaldehydes.

EXAMPLE 12 Preparation of epimeric 5(S )-ethyl-4( R)-quinuclidine-2E-carboxaldehydes A solution containing 1.34 g. of1,1-dichloro-3 [3(S)-ethyl-4(R)-piperidinyl]propan2(S)-ol hydrochloridein ml. of water was combined with 150 ml. of benzene. The stirredmixture was cooled in an icebath and 8.7 ml. of a 1.68N potassiumhydroxide solution was added slowly. Stirring at room temperature wascontinued under an atmosphere of nitrogen for hours. The aqueous layerwas separated and extracted with benzene. The combined organic layer wasdried over sodium sulfate and evaporated under reduced pressure at 30.The residue on evaporative bulb-tobulb distillation at 90 and 0.1 mmHgyielded 500 mg. of liquid epimeric 5(S)-ethyl-4(R)-quinuclidine-2-carboxaldehydes, [0:1 2 '85.56 (c 1.0682, methanol).

Analysis Calcd. for C H NO (167.24); C, 71.81; H, 10.25; N, 8.38; Found:C, 71.55; H, 10.29; N, 8.65.

EXAMPLE 13 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2E-carboxaldehydes A solution containing2.36 g. of a mixture of l,ldichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(S)- ol hydrochlorideand 1,l-dichloro-3-[3(R)-vinyl-4(S)- piperidinyl]propan-2(R)-olhydrochloride in 35 ml. of water was combined with 850 ml. of benzene.The stirred mixture was cooled in an ice bath and 15.4 ml. of 1.68Npotassium hydroxide solution was added slowly under a nitrogenatmosphere. Stirring at room temperature was continued for 16 hours. Theaqueous layer was separated and extracted with benzene. The combinedorganic layers were washed with water, dried over sodium sulfate andevaporated under reduced pressure at 30. The residue on evaporativebulb-tobulb distillation at 60 and 0.05 mml-lg. yielded 767 mg. ofliquid epimeric 5(R)-vinyl-4(S)-quinuclidine- 2.f-carboxaldehydes, [0:]2 +154.85 (c. 0.8957, chloroform).

EXAMPLE 14 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2f-carboxylic acid ethyl esters a. To asolution containing 8.3 g. of racemic 1,1-dichloro-3-[3(R)ethyl-4(S)piperidinyl]propan-2(S)- ol hydrochloride in600 ml. .of methanol cooled to 0 was added dropwise with stirring asolution of 5.04 g. of potassium hydroxide in 23.4 ml. of methanol.After completed addition, the temperature of the mixture was allowed torise to room temperature and stirring was continued overnight. Insolublematerial was removed by filtration, and the solution was added to amixture of l 1.7 g. of silver nitrate and 4.8 g. of sodium hydroxide in200 ml. of water. The reaction mixture, after stirring for 3 hours atroom temperature, was filtered through Celite-Filter Aid and thefiltrate was saturated with hydrogen sulfide. The precipitate wasremoved by filtration through Celite-Filter Aid and the filtrate wasevaporated to dryness. The residue was treated with 500 ml. of ethanol,and the mixture was refluxed for 3 hours. After filtering throughCelite- Filter Aid, the filtrate containing a mixture of epimeric,racemic 4,5-erythro-5-ethylquinuclidine-2 -carboxylic acids wassaturated with anhydrous hydrogen chloride and refluxed overnight. Theprecipitate was removed by filtration, and the filtrate was evaporatedto dryness. The yellow oil obtained was treated with 300 ml. of asaturated aqueous solution of sodium carbonate and extracted five timeswith ether. The combined ether extract was dried over sodium sulfate andevaporated to dryness under reduced pressure. The residue was distilledin a short path distillation apparatus at -75C. (oil bath temperature)under a pressure of 0.3 mmHg. to give 3.81 g. (60 percent) of a liquidmixture of epimeric, racemic 4,5-erythro 5-ethylquinuclidine-2-carboxylic acid ethyl esters.

Gas chromatography on a column of 4 percent PEG 4000 MS on Gaschrom Z atshowed the material to consist of two isomers ma 1:] ratio withretention times of t 8.5 min. and t 9.4 min. A separation of the twoisomers was achieved by preparative gas chromatography. In the massspectrum, both isomers showed a low resolution molecular ion peak at m/e21 l and a base peak at m/e 138.

b. To a solution of 5 m1. of methylene chloride in 70 ml. of anhydroustetrahydrofuran cooled to -70 was added during 1 hour 35 ml. of a 1.66Msolution of nbutyllithium in hexane under an atmosphere of dry nitrogen.The mixture was stirred at the same temperature for 20 minutes, whichwas followed by the dropwise addition of 6.8 g. of racemic 2-[1-benzoyl-3(R)- ethyl-4(S)-piperidinyl]acetaldehyde in 30 ml. ofanhydrous tetrahydrofuran. After 30 minutes, the reaction was quenchedby the addition of 30 ml. of water. The mixture was allowed to warm upto room temperature and was subsequently extracted three times withether.

The combined ether extracts were washed with water, dried over sodiumsulfate and evaporated to dryness. The product (4 g.), a mixture ofracemic, epimeric 1,1- dichloro-3-[ 3( R)-ethyl-4( S )-piperidinyl]propan-2- 01s, was dissolved in 400 ml. of methanol. A solution of 1.8g. of potassium hydroxide in 45 ml. of methanol was added and stirringwas continued for 50 hours at room temperature. Then, the solutioncontaining a mixture of racemic, epimeric4,5-erythro--ethylquinuclidine- 2f-carboxaldehydes was combined with amixture of 2.56 g. of sodium hydroxide and 5.44 g. of silver nitrate in60 ml. of water. The reaction mixture, after being stirred for 3 hoursat room temperature, was filtered through Celite-Filter Aid, and thefiltrate was evaporated to dryness. Complete dryness was ensured by theaddition of an ethanol-benzene solvent mixture to the residue followedby removal of the solvents under reduced pressure. The procedure wasrepeated several times. The residue was extracted repeatedly with hotethanol. The combined extracts were evaporated to dryness and theresidue containing a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2- carboxylic acids, was esterified with4 percent ethanolic hydrogen chloride to give, after usual work-up anddistillation under reduced pressure, 1.8 g. ofa mixture of epimeric,racemic 4,5-erythro- 5- ethylquinuclidine-Zg-carboxylic acid ethylesters.

EXAMPLE 15 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-Z-carboxylic acid methyl esters Amixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2E-carboxylic acids, obtained from 5.53 g. of racemicl,l-dichloro-3-[3(R)-ethyl-4(S)- piperidinyl]propan-2(S)-ol HCl by thereaction sequence outlined previously in Example (a), was dissolved in350 ml. of methanol. Concentrated sulfuric acid (5 ml.) was added, andthe mixture was refluxed overnight. After the addition of another 2 ml.of concentrated sulfuric acid, refluxing was continued for an otherhours. The volume was reduced to approximately 30 ml. by evaporationunder reduced pressure. The resulting residue was rendered alkaline witha saturated aqueous solution of sodium carbonate and diluted withdichloromethane. The insoluble material was removed by filtration anddissolved in the minimal amount of water. The aqueous phase wasextracted three times with dichloromethane and the extracts werecombined with the filtrate. The combined organic layer was dried overpotassium carbonate and evaporated under reduced pressure. The residue,on distillation, gave 2.33 g. (59 percent) of a liquid mixture ofepimeric, racemic 4,5-erythro-5-ethylquinuclidine-2- carboxylic acidmethyl esters, b.p. 8485/0.35 mmHg.

EXAMPLE l6 Preparation of epimeric5(R)-ethyl-4(S)-quinuclidine-2g-carboxylic acid ethyl esters To asolution containing 3.2 g. of a mixture of 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)- ol hydrochlorideand l,l-dichloro-3[3(R)-ethyl-4(S)- piperidinyl]propan-2(R)-olhydrochloride in 350 ml. of methanol cooled to 0 was added dropwise withstirring a solution of 1.95 g. of potassium hydroxide in 21 .7 ml. ofmethanol. Stirring was continued at room temperature overnight. Theinsoluble material was removed by filtration, and the solution was addedto a mixture of 3.96 g. of silver nitrate and 1.85 g. of sodiumhydroxide in 35 ml. of water. The reaction mixture, after stirring for 4hours at room temperature, was filtered through Celite-Filter Aid andthe filtrate was evaporated to dryness. The residue was extracted with200 ml. of boiling ethanol. The extract containing a mixture of epimeric5(R)-ethyl-4(S)-quinuclidine-2fi-carboxylic acids was evaporated tocomplete dryness. The residue was dissolved in 4 percent ethanolichydrogen chloride and the solution was refluxed overnight. Thisprocedure was repeated once more. After removal of the precipitate byfiltration, the filtrate was evaporated to dryness. The residue wasrendered alkaline with a saturated aqueous solution of potassiumcarbonate and extracted three times with ether. The combined etherextracts were dried over potassium carbonate and evaporated to drynessunder reduced pressure. Evaporative bulbto-bulb distillation at 97 and0.05-mmHg of the crude product yielded 1 g. of liquid epimeric 5(R)-ethyl-4(S)-quinuclidine-2-carboxylic acid ethyl ester, [a] D +77.32 (c1.0489, methanol).

Analysis Calcd. for c, H,,No, (211.30); C, 68.21; H, 10.02; N, 6.63;Found: C, 68.47; H, 10.25; N, 6.74.

EXAMPLE 17 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2tf-carboxylic acids hydrochlo'rides Asolution containing 2.15 g. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2- carboxylic acid ethyl esters in ml.of 1N hydrochloric acid was left standing at room temperature for 10days. The solution was washed with ether and evaporated to dryness underreduced pressure. Complete dryness was ensured by repeatedly addingtoluene to the residue and removing the solvent under reduced pressure.The residue was crystallized from ethanolether to give 429 mg. of amixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-Z-carboxylic acids hydrochlorides, m.p.239242.

Analysis Calcd. for C H, NO 'HCl (219.72); C, 54.67; H, 8.26; N, 6.38;Found: C, 54.80; H, 8.35; N, 6.24. v

The concentrated mother liquor was treated again with 1N hydrochloricacid and yielded an additional 353 mg. of a mixture of epimeric, racemic4,5-erythro- 5-ethylquinuclidine-2E-carboxylic acid hydrochlorides.

EXAMPLE 18 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2-carboxylic acid ethyl esters Utilizingthe conditions described in Example 8, 6.48

of 2-[ l-benzoyl-3(R)-vinyl-4(S piperidinyl]acetaldehyde was reactedwith dichloromethyllithium, prepared from 3.7 ml. of methylene chlorideand 55 mmoles of n-butyllithium. The resulting product (4.1 g.), amixture of epimeric 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2-ols, was dissolved in 400 ml. ofmethanol. A solution containing 1 1.9 g. of potassium hydroxide in 20ml. of methanol was added and stirring was continued for 50 hours atroom temperature. The solution containing a mixture of epimeric(R)-vinyl-4(S)-quinuclidine-2- carboxaldehydes was combined with amixture of 2.56 g. of sodium hydroxide and 5.78 g. of silver nitrate in40 ml. of water. The resulting reaction mixture, after being stirred for3 hours at room temperature, was filtered through Celite-Filter Aid, andthe filtrate was evaporated to dryness. Complete dryness was ensured bythe addition of an ethanol-benzene solvent mixture to the residuefollowed by removal of the solvents under reduced pressure. Theprocedure was repeated several times. The residue was extractedrepeatedly with hot ethanol. The combined extract was evaporated todryness and the residue containing a mixture of epimeric 5 R )-vinyl-4(S )'quinuclidine-2- carboxylic acids was partially dissolved in 100 ml.of 8 percent ethanolic hydrogen chloride. The reaction mixture wasstirred at room temperature for 3 days and then evaporated to dryness.The residue was treated again with 100 ml. of 5 percent ethanolichydrogen chloride for hours. The solvent was removed under reducedpressure, and the residue was combined with 100 ml. of a saturatedaqueous solution of potassium carbonate. The mixture was extracted threetimes with ether. The combined ether extracts were dried over sodiumsulfate and evaporated to dryness under reduced pressure. The residuewas distilled in a short path distillation apparatus at 77 (oil bathtemperature) under a pressure of 0.15 mmHg. to give 1.88 g. (36 percent)of liquid epimeric 5(R)-vinyl-4(S)-quinuclidine-2- carboxylic acid ethylesters; [011, +82.2 (c. 1.1, 95% ethanol).

EXAMPLE 19 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2-carboxylic acids A suspension of 310 mg.of epimeric 5(R)-vinyl- 4(S)-quinuclidine-Zfi-carboxylic acid ethylesters in 10 ml. of water was left standing at room temperature. After10 days, a clear solution was obtained. The water was evaporated underreduced pressure, and the residue was sublimed at 165 under a pressureof 0.15 mmHg. to give 210 mg. of very hygroscopic crystalline epimeric5(R)-vinyl-4(S)-quinuclidine-Z-carboxylic acids; [11],, +78.4 (c 0.72,CHCl [a:],, +93.2 (c 0.87, IN NaOl-l) measured immediately and [01],,+80.8 (c 0.87, IN NaOH) after heating the solution at 100 for 16 hours.

EXAMPLE 20 Preparation of racemic dihydroquininone and racemicdihydroquinidinone a. To a solution containing 488 mg. of 4-bromo-6-methoxyquinoline in 20 ml. of anhydrous ether was added under nitrogenat 50 0.45 ml. ofa 2.25M solution of butyllithium in hexane. Thesuspension containing 6-methoxy-4-quinolyllithium was stirred at thistemperature for another 15 minutes and then a solution of 433 mg. of amixture of epimeric, racemic 4,5-erythro5-ethylquinuclidine-2-carboxylic acid ethyl esters in 20 ml. ofanhydrous ether was added over a period of 20 minutes. After stirring at50 for another 1.5 hours, the mixture was warmed to room temperature andhydrolyzed by the addition of water. The aqueous layer was separated andextracted three times with ether. The combined organic solution wasdried over sodium sulfate and evaporated to dryness. The crude productwas chromatographed on silica gel preparative plates with ether assolvent. The plates were run three times. Elution with methanol gave 100mg. of a yellow oil which on further treatment gave 50 mg. of acrystalline mixture of racemic dihydroquininone and racemicdihydroquinidinone. m.p. 8690. b. To 5 ml. of anhydrous ether was added0.67 ml. of 1.66M solution of butyllithium in hexane. The resultingsolution was cooled to and with stirring and under a nitrogenatmosphere, 1 19 mg. of 4-bromo-6- methoxyquinoline dissolved in 5 ml.of ether was added. The suspension containing 6-methoxy-4-quinolyllithium was combined with 56 mg. of 1,4-diazabicyclo[2.2.21octane dissolved in 5 ml. of anhydrous ether and themixture was stirred at 70 for 2 hours. Thereafter, a solution of 126 mg.ofa mixture of epimeric, racemic 4,5erythro-S-ethylquinuclidine2$-carboxylic acid ethyl esters in 5 ml. of anhydrous ether was added.After stirring at 70 for 30 minutes, the mixture was quenched with waterand allowed to warm up to room temperature. The aqueous layer wasseparated and extracted with ether. The combined organic solution wasdried over sodium sulfate and evaporated to dryness to give 184 mg. ofan oil containing racemic dihydroquininone and racemicdihydroquinidinone.

Utilizing the procedure described above, there can be obtained: (a) from7-ch1oro4-quinolyllithium, a mixture of racemic7-chlorodihydrocinchonidinone and racemic 7-chlorodihydrocinchoninone,m.p. 124127;

b. from 6-methyl-4-quinolyllithium, a mixture of racemic6methyldihydrocinchonidinone and racemic 6'methyldihydrocinchoninone,m.p. l05l08;

c. from 6-chloro-4-quinolyllithium, a mixture of racemic6chlorodihydrocinchonidinone and racemic 6'- chlorodihydrocinchoninone,m.p. 104-l07;

d. from 7-methoxy-4-quinolyllithium, a mixture of racemic7'methoxydihydrocinchonidinone and racemic 7methoxydihydrocinchoninone,m.p. 1l1-1l7; and the like.

EXAMPLE 21 Preparation of racemic dihydroquinine and racemicdihydroquinidine from a mixture of racemic dihydroquininone and racemicdihydroquinidinone To a solution of 5.06 g. of a crystalline mixture ofra cemic dihydroquininone and dihydroquinidinone in 500 ml. of drybenzene was added dropwise 12.5 ml. of a 25 percent solution ofdiisobutylaluminum hydride in toluene with stirring under an atmosphereof dry nitrogen. After approximately 30 minutes, the reaction wasquenched by the addition of 2 ml. of methanol-water 1:1 The precipitatedalumina was separated by filtration and washed thoroughly with methanol.The residue of the methanol washings (3.87 g.) was crystallized fromacetone yielding 3.14 g. (61 percent) of racemic dihydroquininemonohydrate in three crops. The residue of the benzene solution (1.54g.) was crystallized from a concentrated solution in ethanol yielding579 mg. (11 percent) of racemic dihydroquinidine in four crops. Afterpurification on preparative tlc (chloroform-triethylamine-methanol,85:10:5) more 01,1- dihydroquinidine and a,l-dihydroquinine could becrystallized from ethanol and acetone, respectively.

Utilizing the procedure described above:

a. from a mixture of racemic 7 chlorodihydrocinchonidinone and racemic7- chlorodihydrocinchoninone, there can be obtained racemic7-chlorodihydrocinchonidine, m.p. 192193, and racemic7chlorodihydrocinchonine, m.p. 251-253 dec.;

b. from a mixture of racemic 7-methoxydihydrocinchonidinone and racemic7-meth0xydihydrocinchoninone, there can be obtained racemic7'-methoxydihydrocinchonidine, m.p. 160, and racemic7-methoxydihydrocinchonine, m.p. 217219;

c. from a mixture of racemic 6-methyldihydrocinchonidinone and racemic6-methyldihydrocinchoninone, there can be obtained, racemic6'-methyldihydrocinchonidine, m.p. 216-218, and racemic6methyldihydrocinchonine, m.p. 153.5-155;

d. from a mixture of racemic 6- chlorodihydrocinchonidinone and racemic6'- chlorodihydrocinchoninone, there can be obtained racemic6'-chlorodihydrocinchonidine, m.p. 100102, and racemic6'-chlorodihydrocinchonine, m.p. 172.5-173.5.

EXAMPLE 22 Preparation of Quinine and Quinidine To 100 ml. of anhydrousether there was added 14.5 ml. of a 1.45M solution of n-butyllithium inhexane. The resulting solution was cooled to 70 and with stirring asolution of 4.76 g. of 4-bromo-6- methoxyquinoline in 100 ml. ofanhydrous ether was added under an atmosphere of dry nitrogen. Theyellow suspension of 6-methoxy-4quinolyllithium in ether whichimmediately formed was stirred at 70 for 2 hours. A solution of 2.1 g.of epimeric (R)-vinyl-4(S)- quinuclidine-2-carboxylic acid ethyl estersin 100 ml. of anhydrous ether was added, and after 30 mins., thereaction was quenched by the addition of water and allowed to warm up toroom temperature. The ethereal solution was washed with water, driedover sodium sulfate and evaporated to dryness under reduced pressure toyield 5.08 g. of an oil which contained a mixture of quininone andquinidinone. To a cooled solution of 4.74 g. of the above material in100 ml. of anhydrous benzene, there was slowly added 13 ml. of a 25percent solution of diisobutylaluminum hydride in toluene under anatmosphere of dry nitrogen. The reaction was quenched after 1 hour bythe addition of ml. of water-methanol (1:1) with vigorous stirring. Theprecipitate which formed was collected by filtration and washedthoroughly with methanol. The filtrate was dried over anhydrous sodiumsulfate and evaporated to dryness. A solution of the residue inchloroform was washed successively with 1N sodium hydroxide and water,dried over anhydrous sodium sulfate and evaporated to dryness. Theproduct (4.1 g.) was chromatographed on 150 g. of neutral alumina(Woelm, activity I) with ethyl acetate-benzene (1:1 (500 ml.), ethylacetate (800 ml.) and methanol (400 ml.) as eluent. Evaporation of themethanol fraction gave 2.5 g. of

product which was chromatographed on silica gel preparative plates (20 X20 X 0.2 cm.) with chloroformtriethylaminemethanol (85:lO:5) asthesolvent mixture. Elution of the lowest of three major bands withchloroform-methanol (1:1) gave 289 mg. of a yellow oil which wasdissolved in ethanol, and on treatment with 44 mg. of d-tartaric acid inethanol yielded the crystalline, neutral tartrate of quinine, m.p.2142l5, [a],, l49 (c, 0.985, MeOH). The compound showed ir-spectrum andtlc R -value identical with those of an authentic sample. The meltingpoint was not depressed on admixture with an authentic specimen. Elutionof the middle band with methanolchloroform (1:1) gave 311 mg. ofquinidine, which after recrystallization from ethanol and drying atunder reduced pressure for 15 hours showed m.p. l70172, [a],, 261 (c,0.995, ethanol). The irspectrum and the tlc R value were identical withthose of authentic material. No depression of the melting point wasobserved on admixture with an authentic sample. The upper band, uponelution with methanolchloroform (1:1) yielded 95 mg. of oily residuewhich was identical with an authentic mixture of epiquinine andepi-quinidine.

Utilizing the reaction conditions described above:

a. from 7-chloro-4-quinolyllithium, there can be obtained,7'-chlorocinchonidine, m.p. 177-l79, and 7'- chlorocinchonine, m.p.245246;

b. from 6,8dichloro-4-quinolyllithium, there can be obtained,6,8'-dichlorocinchonidine, m.p. 105l08, and 6',8'-dichlorocinchoninedihydrochloride monohydrate, m.p. 250 dec.;

c. from 6chloro-4quinolyllithium, there can be obtained,6-chlorocinchonidine, m.p. l93-l94, and 6'- chlorocinchonine, m.p. 154-l55;

(1. from 4-quinolyllithium, there can be obtained, cinchonidine anclcinchonine.

EXAMPLE 23 Preparation of Quinine and Quinidine To 30 ml. of anhydrousether was added 2.74 ml. of a 1.62M solution of butyllithium in hexane.The resulting solution was cooled to -70. With stirring under a nitrogenatmosphere, a solution of 1.08 g. of 4-bromo- 6-methoxyquinoline in 30ml. of anhydrous tetrahydrofuran was added. After stirring the mixturecontaining 6-methoxy-4-quinolyllithium for 30 minutes at 70, a solutionof 748 mg. of freshly distilled 5(R)-vinyl-4(S)-quinuclidine-Zfi-carboxaldehyde in 15 ml. of anhydrous ether was addedover a period of 30 minutes After the addition was completed, stirringwas continued for two hours at 70. The reaction mixture then washydrolyzed by the addition of water and extracted several times withether. The organic extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The residue waschromatographed on Merck F-254 silica gel preparative plates withchlorofor'mtriethylamine-methanol 10:5) as the solvent mixture. Elutionof three separate bands and purification of the eluates yielded 215 mg.of quinidine [mp l72--173; [041 265.6 (c 1.07, percent ethanol)], 220mg. of the neutral d-tartrate of quinine [mp 21 1 212"; hf? 159.5 (c1.00, methanol)], and 330 mg. of a mixture of epiquinine and'epi-quinidine.

EXAMPLE 24 Preparation of racemic 6,8'-diehlorodihydrocinchonidinedihydrochloride and racemic 6',8'-dichlorodihydrocinchoninedihydrochloride a. To 500 ml. of anhydrous ether was added 38 ml.

of 1.45M solution of butyllithium in hexane. The resulting solution wascooled to 68 and with stirring and under a nitrogen atmosphere 13.8 g.of 4-bromo-6,8- dichloroquinoline dissolved in 175 ml. of anhydroustetrahydrofuran was added over a period of 30 minutes. Subsequently, asolution of 5.3 g. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2- carboxylic acid ethyl esters in 250ml. of anhydrous ether was added to the 6,8-dichloro-4-quinolyllithium,thus prepared, and stirring was continued for 1 hour at 70. The reactionwas then quenched by the addition of water and allowed to warm up toroom temperature. The organic solution was washed with water, dried oversodium sulfate and evaporated to dryness under reduced pressure to yield19.0 g. of an oily residue containing a mixture of racemic 6',8'-dichlorodihydrocinchonidinone and racemic 6,8'-dichlorodihydrocinchoninone. This material was dissolved in 250 ml. ofanhydrous benzene and cooled. To the cooled solution there was addedover a period of minutes 17 ml. of a 25% solution of diisobutylaluminumhydride in toluene under an atmosphere of dry ni trogen. The reactionmixture was stirred for one hour at room temperature and then quenchedby the addi tion of 20 ml. of water-methanol 1:1 The precipitate wascollected by filtration and washed thoroughly with methanol. A solutionof the residue in chloroform was washed with 1N sodium hydroxide andwater. The or- -ganic solutions were combined, dried over sodium sulfateand evaporated to dryness under reduced pressure. The resulting product(14.1 g.) was chromatographed on 500 g. of neutral alumina (Woelm,activity I) with ethyl acetate (1.8 1.) followed by methanol (2.2 l.) asthe eluent. Evaporation of the methanol fractions yielded 5.27 g. ofproduct which together with 6.9 g. of material obtained previously waschromatographed on 700 g. of silica gel (Silica Gel 0.05 0.2 mm.; id ofcolumn 55 mm.). Fractions of 250 ml. each were collected. Afterfractions with chloroformtriethylamine (97:3) as the liquid phase, thecomposition of the eluent was changed to 96:4. Fractions 29 40 werecombined, evaporated to dryness and the residue was dissolved indichloromethane. The organic solution was washed twice with water, driedover sodium sulfate and evaporated to dryness under reduced pressure.Crystallization of the residue (1.79 g.) from a mixture of benzenehexane(1:2) gave 1.3 g. of crystalline, racemic 6,8-dichlorodihydrocinchonine. Recrystallization from benzene-hexane(1:1) and drying of the sample at 80 under reduced pressure to constantweight yielded racemic 6',8'- dichlorodihydrocinchonine, containing A;mole of benzene: m.p. 172-173.

Analysis Calcd. for C H C1 N O A: C H (391.35); C, 64.45; H, 6.18; N,7.15; Cl, 18.12; Found: C, 64.63; H, 6.42; N, 7.28; Cl, 18.46.

The dihydrochloride salt of 6 ',8 dichlorodihydrocinchonine was preparedby dissolving 1.05 g. of the free base in a minimal amount of ethanolichydrogen chloride. Upon addition of ether to the solution, 1.0 g. ofcrystalline racemic 6',8'- dichlorodihydrocinchonine dihydrochlorideprecipitated, m.p. 210212. Upon two recrystallizations fromethanol-ether the melting point was 214215 (dried for 100 minutes at 80under reduced pressure).

Analysis Calcd. for C H Cl N Q2HCl (438.22); C, 52.07; H, 5.52; N, 6.39;Cl, 32.36; Found: C, 52.14; H, 5.56; N, 6.42; Cl, 31.90.

Fractions 42 57 were combined and evaporated to dryness. The residue wasdissolved in dichloromethane. The solution was washed twice with water,dried over sodium sulfate and evaporated to dryness under re ducedpressure. The residue (1.56 g.) was dissolved in the minimal amount ofethanolic hydrogen chloride and upon addition of ether to the solution1.15 g. of crystalline racemic 6,8'-dichlorodihydrocinchonidinedihydrochloride was precipitated. Recrystallization from methanol-etheryielded analytically pure racemic 6',8'-dichlorodihydrocinchonidinedihydrochloride, m.p. 226-227.

Analysis Calcd. for C H C1 N O2HCl (438.22); C, 52.07; H, 5.52; N, 6.39;Cl, 32.36; Found: C, 52.04; H, 5.63; N, 6.29; CI, 32.17.

b. To 500 ml. of anhydrous ether was added 38 ml. of 1.45M solution ofbutyllithium in hexane. The resulting solution was cooled to and withstirring and under a nitrogen atmosphere, 13.8 g. of 4-bromo-6,8-dichloroquinoline dissolved in 200 ml. of anhydrous tetrahydrofuran wasadded. Stirring of the solution of 6,8-dichloro-4-quinolyllithium wascontinued at 70 for another 10 minutes, followed by the addition of 5.6g. of anhydrous tetramethylethylenediamine dissolved in 250 ml. ofanhydrous ether. After additional stirring for 15 minutes, there wasadded 5.8 g. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2- carboxylic acid ethyl ester dissolvedin 250 ml. of anhydrous ether. The mixture was stirred at 70 for 1 hour,then quenched by the addition of water and allowed to warm up to roomtemperature. The organic solution was washed with water, dried oversodium sulfate and evaporated to dryness under reduced pressure to yield17.5 g. of an oily residue containing a mixture of racemic6,8'-dichlorodihydrocinchonidinone and racemic6',8'-dichlorodihydrocinchoninone. Subsequent conversion to racemic6',8'-dichlorodihydrocinchonidine dihydrochloride and6',8'-dichlorodihydrocinchonine was carried out as described in (a)above.

Utilizing the reaction conditions described above:

a. from 6,7-dimethoxy-4-quinolyllithium there can be obtained, racemic6,7-dimethoxydihydrocinchonidine dihydrochloride, m.p. 208-210 dec., andracemic 6',- 7-dimethoxydihydrocinchonine dihydrochloride, m.p. 221225;

b. from 6,7-methylenedioxy-4-quinolyllithium, there can be obtainedracemic 6',7-methylenedioxydihydrocinchonidine, m.p. 232233, and racemic6',7'- methylenedioxydihydrocinchonine, m.p. 234235.

EXAMPLE 25 Preparation of racemic dihydroquinine and racemicdihydroquinidine To 30 ml. of anhydrous ether was added 2.22 ml. of a2.25M solution of butyllithium in hexane. The resulting solution wascooled to 68C. and with stirring under a nitrogen atmosphere 1.19 g. of4-bromo-6- methoxyquinoline was added. Immediately, a yellow suspensionof 6-methoxy-4-quinolyllithium was formed. To this suspension was addedwithin minutes a solution of 1.42 g. of the crude mixture of epimeric,

racemic 4,S-erythro-S-ethylquinuclidine-2- carboxaldehydes in 30 ml. ofanhydrous ether. After the addition was completed, stirring wascontinued for 1 hour at 65C. The reaction mixture was then poured intoan ice-water slurry and extracted with dichloromethane. Thedichloromethane extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The residue thus obtained wasdissolved in dichloromethane and the solution was extracted twice with2N hydrochloric acid. The acidic extract was washed with dichloromethaneand then made alkaline by the addition of 6N aqueous sodium hydroxide.The free bases thus liberated were extracted into dichloromethane. Theextract was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness to give'crude oily product. The crude product waschromatographed on Merck F-254 silica gel preparative plates withchloroform-triethylaminemethanol (85: 10:5) mixture. Elution of twoseparated bands gave racemic dihydroquinidine, m.p. l53l55 and racemicdihydroquinine, m.p. l7l l72.

EXAMPLE 26 Preparation of racemic 6,7'methylenedioxydihydrocinchonidineand racemic 6',7'methylenedioxydihydrocinchonine To 250 ml. of anhydrousether was added 19.3 ml. of a 1.45M solution of n-butyllithium inhexane. The resulting solution was cooled to 68. Thereafter, there wasadded 6.55 g. of 4-bromo-6,7- methylenedioxyquinoline dissolved in 200ml. of anhydrous tetrahydrofuran over a period of 30 minutes withstirring and under a nitrogen atmosphere to afford 6,7-methylenedioxy-4-quinolyllithium. Stirring of the mixture was continuedat the same temperature for 30 minutes followed by the addition of asolution of 2.15 g. of a mixture of epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2e-carboxaldehydes in 250 ml. of ether over a periodof] hour. The reaction mixture was stirred at 70 under a nitrogenatmosphere overnight. After quenching with water, the mixture wasallowed to warm to room temperature and subsequently was concentratedunder reduced pressure. The residue was dissolved in ether. The etherealsolution was washed with water, dried over sodium sulfate and evaporatedto dryness to give 6.54 g. of an oil. Chromatography on neutral alumina(Woelm, activity 1) with ethyl acetate yielded 2.97 g. of a yellowsolid. Subsequent elution' with methanol yielded 3.37 g. of a brown oil.This was chromatographed on silica gel preparative plates X 20 X 0.2 cm)with ethyl acetate-triethylamine (97:3) as the solvent mixture. Theplates were developed three times. Elution of the lowest major band withmethanolchloroform and crystallization of the eluate (510 mg.) fromacetone gave racemic 6,7-methylenedioxydihydrocinchonidine, m.p. 232233.Elution of the next higher band with methanolchloroform andcrystallization of the eluate (597 mg.) from acetone gave racemic6,7'-methylenedioxydihydrocinchonine, m.p. 234235.

Analysis Calcd. for C H N O (340.41); C, 70.56; H, 7.11; N, 8.23; Found:C, 70.25; H, 7.29; N, 8.05.

Utilizing the procedure described above:

a. from 6-methyl-4-quinolyllithium, there can be obtained racemic6methyldihydrocinchonidine, m.p.

216-2l8 and racemic 6'methyldihydrocinchonine, m.p. l53.5l55;

b. from 6-chloro-4-quinolyllithium, there can be obtained racemic 6chlorodihydrocinchonidine, m.p. lO0-l02, and racemic6chlorodihydrocinchonine, m.p. l72.5l73.5;

c. from 6,7dimethoxy-4-quinolyllithium, there can be obtained racemic6,7-dimethoxydihydrocinchonidine dihydrochloride, m.p. 2082l0 dec., andracemic 6,7dimethoxydihydrocinchonine dihydrochloride, m.p. 22l225;

d. from 7-methoxy-4-quinolyllithium, there can be obtained racemic7methoxydihydrocinchonidine, m.p. 160, and racemic7'-methoxydihydrocinchonine, m.p. 2l72l9;

e. from 6,8dichloro-4-quinolyllithium, there can be obtained racemic6',8dichlorodihydrocinchonidine dihydrochloride, m.p. 226-227, andracemic 6,8- dichlorodihydrocinchonine dihydrochloride, m.p. 214-2l5.

EXAMPLE 27 Preparation of racemic 7chlorodihydrocinchonidine and racemic7-chlorodihydrocinchonine To a solution of 5.2 ml. of 1.62M butyllithium(in hexane) in 40 ml. of anhydrous ether and 10 ml. of anhydroustetrahydrofuran was added at under an atmosphere of nitrogen, 2.1 g. of4-bromo-7- chloroquinoline dissolved in 30 ml. of anhydroustetrahydrofuran. Stirring of the mixture containing7chloro-4-quinolyllithium was continued at the same temperature for 30minutes followed by the addition of a solution of 1.4 g. of a mixture ofepimeric, racemic 4,5-erythro-5quinuclidine-2g-carboxaldehydes in 20 ml.of anhydrous ether. The reaction mixture was stirred at 70 for 2 hours.After quenching with water, the mixture was allowed to warm to roomtemperature. The aqueous layer was separated and extracted twice withether. The combined organic extract was dried over sodium sulfate andevaporated to dryness under reduced pressure. The residue waschromatographed on 300 g. of silica gel (Merck 70-325) withchloroform-triethylamine as the liquid phase to afford racemic7'-chlorodihydrocinchonidine, mp l88l90 after recrystallization fromacetone (mixture mp with an authentic sample l88l90), and racemic 7'-chlorodihydrocinchonine, mp 25l-252 after recrystallization from ethanol(mixture mp with an authentic sample 25l252).

' EXAMPLE-28 Preparation of Dihydroquinine and Dihydroquinidine To 20ml. of anhydrous ether was added 1.98 ml. of a 1.62M solution ofbutyllithium in hexane. The resulting solution was cooled to 70 and withstirring under a nitrogen. atmosphere a solution of 760 mg. of4-bromo-6-methoxyquinoline in 20 ml. of anhydrous tetrahydrofuran wasadded. After stirring the mixture containing 6-methoxy-4-quinolyllithiumfor 30 minutes at 70, a solution of 538 mg. of freshly distilled 5(R)-ethyl-4(S)-quinuclidine-ZE-carboxaldehyde in 10 ml. of anhydrous etherwas added during 15 minutes. After completion of the addition, stirringwas continued for two hours .at 70. The reaction mixture then washydrolyzed by theaddition of water, allowed to warm up to roomtemperature and diluted with an equal volume of ether. The aqueous layerwas separated and extracted three times with 15 ml. of ether each. Thecombined organic extract was dried over sodium sulfate and evaporated todryness. The residue was chromatographed on silica gel plates (MerckF-254) with chloroform-triethylamine-methanol (85:l0:5) as the solventmixture. Elution of the lowest of the major bands withchloroformmethanol l :l gave 138 mg. of dihydroquinine, mp l69170 afterrecrystallization from chloroform-ether, [011 2 144.5 (c 0.935, 95percent ethanol). The melting point was not depressed on admixture witha natural sample. Elution of the next higher band withchloroform-methanol (1:1) gave 210 mg. of an oil which was dissolved inethanol. Upon standing, crystalline dihydroquinidine separated, mpl69-l70 (mixed up with natural material l69l70) M1 2 222 (c 0.970,ethanol). From the third band elution with chloroform-methanol (lzl)yielded 87 mg. of a mixture of dihhydropiquinine anddihydroepiquinidine. The mixture was dissolved in benzene and treatedwith 48 mg. of dibenzoyl-d-tartaric acid in benzene-acetone. Thesolvents were evaporated to dryness and the residue afterrecrystallization from benzene yielded the neutral dibenzoyl-d-tartrateof dihydroepiquinidine, mp l68l70, [oz] 2 l3.7 [c 0.970,ethanolchloroform (4:1)].

Example 29 Tablet Formulation J2EE Racemic 7'-methoxydihydrocinchonine25.00 mg. Dicalcium Phosphate Dihydrate,

unmilled 175.00 mg. Corn Starch 24.00 mg. Magnesium Stearate L mg. TotalWeight 225.00 mg.

Procedure Example 30 Capsule Formulation Per Capsule Racemic7-methoxydihydrocinchonine 50 mg. Corn Starch, U.S.P. 150 mg. Talc.U.S.P. 10 mg. Total Weight 210 mg.

Procedure Fifty parts of racemic 7-meth0xy-dihydrocinchonine were mixedwith 150 parts of corn starch in a suitable mixer. The mixture wasfurther blended by passing through a Fitzpatrick Comminuting Machinewith a No. 1A screen with knives forward. The blended powder wasreturned to the mixer and 10 parts of talc were added and blendedthoroughly. The mixture was filled into No. 4 hard shell gelatincapsules on a Parke Davis capsulating machine.

Example 3l Suppository Formulation Per 13 Grn. Suppository Racemic7-methoxydihydrocinchonidine 0.025 gm. Hydrogenated Coconut Oil 1.230gm. Carnauba Wax 0.045 gm.

Procedure 123 Parts of hydrogenated coconut oil (Wecobee M- E. F. DrewCo., New York, New York) and 4.5 parts of carnauba wax were melted in asuitable size glass lined container (stainless steel may also be used),mixed well and cooled to 45C. 2.5 Parts of racemic 7methoxydihydrocinchonidine, which had been reduced to a fine powder withno lumps, was added and stirred until completely and uniformlydispersed. The mixture was poured into suppository molds to yieldsuppositories having an individual weight of 1.3 gms. The suppositorieswere cooled and removed from molds and individually wrapped in wax paperfor packaging.

We claim:

1. A process for preparing an epimeric compound of the formula wherein Ris lower alkyl of 1 to 7 carbon atoms or benzyl and R is as previouslydescribed enantiomer or racemate thereof, with a 4-quinolyllithiumcompound of the formula 5. A process in accordance with claim 3, whereinR is trifluoromethyl, chlorine, methoxy or methylenedi- 6. A process inaccordance with claim 4, wherein R is chlorine, trifluoromethyl, methoxyor methylenedioxy.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. I 3,907,806 Q DATED September 23, 1975 INVENTOR(S Guenter Grethe and MilanRadoje Uskokovic It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 34, hnes 62-67 should be:

Signed and Scaled this a ty-fift Day 'of May 1976 [SEAL] Arrest.

i RUTH c. msou c. MARSHALL DANN Arresting Officer Commissioner ofParents and Trademarks

1. A PROCESS FOR PREPARING AN EPIMERIC COMPOUND OF THE FORMULA
 2. Aprocess in accordance with claim 1, wherein the reaction is carried outat a temperature in the range of about 0* to about -70*C.
 3. A processin accordance with claim 2, wherein R2 is ethyl.
 4. A process inaccordance with claim 2, wherein R2 is vinyl.
 5. A process in accordancewith claim 3, wherein R1 is trifluoromethyl, chlorine, methoxy ormethylenedioxy.
 6. A process in accordance with claim 4, wherein R1 ischlorine, trifluoromethyl, methoxy or methylenedioxy.